1. Technical Field of the Invention
This invention is directed to a process for the electrochemical reduction of 7-ketolithocholic acid to ursodeoxycholic acid (UDCA). The invention also concerns a process for the conversion of chenodeoxycholic acid (CDCA) to UDCA by the oxidation of CDCA to 7-ketolithocholic acid and simultaneous electrochemical reduction of 7-ketolithocholic acid to UDCA.
2. Description of the Prior Art
Chenodeoxycholic acid and its epimer ursodeoxycholic acid, are recognized as having the important medicinal activity of dissolving gallstones present in mammals. While chenodeoxycholic acid has recently been approved for use in the United States to dissolve gallstones, ursodeoxycholic acid is potentially more important since the dosage required to effectively dissolve gallstones is much less than that required of chenodeoxycholic acid. It, therefore, would be desirable to provide a process whereby ursodeoxycholic acid could be prepared in substantially pure form.
The asymmetrical reduction of hindered carbonyl compounds is usually strongly influenced by the preferred direction of approach of the reducing agent. In the case of 7-ketolithocholic acid, the oxidation product of chenodeoxycholic acid, that preferred approach gives back predominantly chenodeoxycholic acid, with only small amounts of ursodeoxycholic acid. For this reason, processes for reduction which give predominantly ursodeoxycholic acid are very important. The prior art contains disclosures of procedures for the production of ursodeoxycholic acid by the reduction of 7-ketolithocholic acid using sodium or potassium in alcohol solvents (see, e.g., French Pat. Nos. 1,391,735 and 1,372,109 and Chem. Ab. 87, 168276n), but use of these dangerous chemicals on the industrial scale is quite hazardous.
The stereoselective reduction of some steroidal non-conjugated ketones has been reported by Kobasakalian et al, J. Org. Chem. 26, 1738 (1961). Ketones at the 3, 6, 11, 12 and 17 positions afforded the equatorial isomer. Electrochemical reduction of certain ketones, including sterically hindered ketones, is treated in the work of Utley and his co-workers: Coleman et al, Chem. Commun. 1971 p. 104; Holman et al, Tetrahedron Letters, 1974 p. 1553; Coleman et al, J. Chem. Soc. Perkins II, 1976 p. 879; Holman et al, J. Chem. Soc. Perkins II, 1976 p. 884. In this work, sterically hindered ketones showed an increased tendency to give reduction to alkanes. Reduction in acidic solution also leads to the formation of methylene groups at the carbonyl location. Throop et al, J. Am. Chem. Soc., 89, p. 4790 (1967).